MIRA: Atropisomerism as a means to increase target selectivity and as inspiration for new chemistry

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The major goal of our research program is to exploit atropisomerism as a design principle to increase the selectivity of promiscuous biologically active small molecules. Atropisomerism is a form of chirality that arises from differential substitution around a bond where the rotational conformers are enantiomers. Atropisomerism differs from traditional `point' chirality in that racemization can occur via bond rotation, and thus depending on the degree of hindrance to rotation around this bond, atropisomers can exist as stable isolable enantiomers or interconverting atropisomeric mixtures. Many biologically active small molecules exist as rapidly interconverting atropisomers, yet bind to their biological targets in an atropisomer-specific manner, with the other atropisomer contributing little to the desired activities. This has led us to hypothesize that the design of analogs of promiscuous biologically active compounds that are locked into a single atropisomer will have increased target selectivity due to preclusion of off-target effects caused by the other atropisomer. In support of this hypothesis we have obtained preliminary results in which atropisomerically pure analogs of promiscuous kinase inhibitors (KIs) possessed improved kinase selectivity. This is impactful because kinases are one of the most important drug targets in oncology, however a significant amount of conservation throughout the kinome has rendered most KIs unselective. This promiscuity can lead to side effects in patients. These issues are exemplified by RET kinase, a validated therapeutic target for numerous cancers for which no selective inhibitor exists. In the first part of this application we propose to optimize the structure of lead `atropisomer preorganized' (AP) KIs for potency and selectivity towards RET. The expected outcome of these studies will be a set of selective RET inhibitors as leads towards cancer therapeutics with fewer side effects and as valuable chemical probes that can be used to better understand RET's roles in these cancers. Moving forward we also propose a broader application of AP to other target kinases and classes of promiscuous inhibitor such as mimetics of -helices. Access to atropisomerically pure analogs is currently a major bottleneck in the field. While preparative `chiral HPLC' can provide enantiopure analogs for initial studies, the throughput of material is relatively modest and inefficient. Because of this, a second long-term goal of our research program is the development of new catalytic atroposelective methodologies that allow for the incorporation of diverse substitutions into diverse classes of atropisomer. In support of this we have preliminary results for several novel reactions that allow for the incorporation of several different groups adjacent to an atropisomeric axis. In this MIRA we seek to optimize these reactions and extend these reactivities to challenging pharmaceutically relevant atropisomeric scaffolds. The expected outcomes of these studies will be first-in-class routes towards several classes of atropisomer that will expedite the study of the effects of atropisomer conformation in drug discovery.